First Report of Scedosporium aurantiacum Endocarditis in an Immunocompetent Chinese Male and Literature Review

Introduction

Scedosporium species are saprophytic filamentous fungi broadly distributed in soil, sewage, and sludge that can cause asymptomatic colonization or localized or disseminated infection in immunocompromised patients, especially following aspiration of contaminated water or traumatic inoculation.¹ Scedosporium aurantiacum, one of the main species responsible for scedosporiosis, is a rare and life-threatening opportunistic pathogen that has intrinsic resistance to multiple antifungals, presenting significant challenges to the processes of diagnosis and treatment.² S. aurantiacum had a high incidence in respiratory specimens of cystic fibrosis patients in Australia, and a relatively low incidence in Europe.³ The clinical isolates of S. aurantiacum from China were described for the first time in 2022,⁴ but so far there has been no clinical case report of S. aurantiacum endocarditis in China. Herein, we report the fatal case of a previously healthy Chinese patient with disseminated infection and endocarditis, which was found to be caused by S. aurantiacum using fungal culture, MALDI-TOF MS, and nanopore sequencing technology. We also provide a literature review on S. aurantiacum infections.

Case Presentation

A 44-year-old previously healthy Chinese male presented to our hospital with progressive back pain and limited functional activity of the left lower limb for one month. He reported no history of immunosuppressive medication, corticosteroid, or intravenous drug addiction. On admission, he was conscious, and his vital signs and physical examination findings were unremarkable, except for a lumbosacral examination, which revealed tenderness in the interspinous and bilateral paravertebral muscles, accompanied by radiating pain in his left lower limb. The complete blood cell count showed a white blood cell count (WBC) of 13.36×10⁹/L with neutrophils 80.1%, hemoglobin (Hb) 94 g/L, and platelets (PLT) 870×10⁹/L. Elevated inflammatory marker levels included high-sensitivity C-reactive protein (hsCRP) 277.77 mg/L, erythrocyte sedimentation rate (ESR) 88 mm/h, interleukin-6 (IL-6) 53.1 pg/mL and procalcitonin (PCT) 204.27 ng/mL. HIV-1/-2 antibody test results were negative.

Lumbar magnetic resonance imaging revealed inflammation of the L4/5 disc and ruled out the possibility of an intraspinal tumor. He immediately underwent an aggressive surgical debridement and etiological investigation, but no pathogenic bacteria, including Brucella and mycobacteria, were identified. Subsequently, histopathological of the L4/5 nucleus pulposus revealed granulomatous inflammation. His serum (1-3)-β-D-glucan antigen assay (BG assay) and serum aspergillus galactomannan antigen assay (GM assay) came back negative. Piperacillin/tazobactam and vancomycin were empirically administered. However, the symptoms did not improve. Even worse, his body temperature increased to 40 °C, accompanied by new symptoms of chest tightness and dyspnea. Therefore, the indicators of cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-pro BNP) were investigated. The results showed that the values significantly increased, reaching 40.52 pg/mL and 2379 pg/mL, respectively. Then, echocardiography was performed and revealed new-onset vegetation measuring 13×12 mm over the native mitral valve, with severe mitral regurgitation (Figure 1A). Based on the unusual finding, a detailed interview was conducted once more with the patient. We learned that he had a history of falling into a nearly dry wastewater pool after exposure to hydrogen sulfide gas while working at a sewage treatment plant three months ago. Accordingly, serum BG assay was re-examined and found to be positive with 126.59 pg/mL (normal <70 pg/mL), whereas GM assay remains negative. Therefore, fungal endocarditis was clinically suspected.

Figure 1 (A) Echocardiography showing a large vegetation over the native mitral valve (white arrow). S. aurantiacum cultured on Sabouraud dextrose agar after 3 days at 35 °C: (B) front view and (C) reverse view. (D) Phenotypic characterization of S. aurantiacum colonies on Sabouraud dextrose agar after 5 days at 35 °C. (E) Lactophenol cotton blue stain (×1000) of S. aurantiacum showing septate hyphae with obovoid and thick-walled conidia.

According to the diagnostic protocol for infective endocarditis (IE), two sets of aerobic and anaerobic blood cultures (from veins of the left lower extremity and the right upper extremity, respectively) were collected, and four days apart two other sets (from the right femoral vein and the left femoral artery, respectively) were collected. As expected, branching hyphae were found in all aerobic blood culture smears. At 35 °C, the colonies appeared mold-like and greyish-white on Sabouraud dextrose agar (SDA) after 3 days of incubation (Figure 1B), and a brown orange center with a distinctive light-yellow pigment appeared on the reverse side of the SDA plate (Figure 1C). Moreover, a concentric growth pattern and white margins of the colonies were observed after 5 days of incubation (Figure 1D). Lactophenol cotton blue staining of the mold revealed septate hyphae with branching at acute angles and lateral cylindrical or slightly flask-shaped conidiogenous cells bearing obovoid and thick-walled conidia singly or in small groups (Figure 1E), morphologically consistent with Scedosporium species.⁵ By using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF MS) (Bruker Daltonics GmbH Microflex LT/SH, USA), the fungus was identified as Scedosporium aurantiacum with 2.012 points (Figure 2). Nanopore sequencing targeting the fungal internal transcribed spacer 1 (ITS1) region was conducted using the Oxford Nanopore Technologies (ONT) platform. The fungal sequences showed 100% sequence identity with those of S. aurantiacum (accession number: KP132662), and the sequences were deposited in GenBank (accession number: PX279226) (https://www.ncbi.nlm.nih.gov/nuccore/PX279226.1/). In addition, the lumbar drainage fluid was subjected to prolonged incubation and the fungi grew, but only a single colony. The patient was diagnosed with disseminated S. aurantiacum infection and endocarditis, meeting two major criteria and one minor criterion of the 2023 European Society of Cardiology modified diagnostic criteria for IE.⁶

Figure 2 MALDI-TOF MS analysis of the isolate.

In vitro antifungal susceptibility testing was performed by a broth microdilution assay according to the Clinical and Laboratory Standards Institute guidelines.⁷ The minimum inhibitory concentrations were as follows: voriconazole, 0.5 μg/mL; itraconazole, 1 μg/mL; posaconazole, 2 μg/mL; isavuconazole, 4 μg/mL; caspofungin, 8 μg/mL; anidulafungin, >8 μg/mL; amphotericin B, >16 μg/mL; micafungin, >16 μg/mL; fluconazole, 32 μg/mL and 5-flucytosine, >64 μg/mL.

Owing to his poor clinical status, which manifested as septic shock, multiple organ failure, and a low PLT count of 27×10⁹/L, he was considered unsuitable for surgical management. Intravenous voriconazole (400 mg on day 1 and 200 mg daily thereafter) combined with amphotericin B (Lipid Complex) (200 mg once daily) and other supportive treatments were initiated; however, his condition continued to deteriorate, and he died 12 days after the fungus was isolated. The patient’s family refused autopsy.

Discussion

Although IE due to Scedosporium species is quite rare, it is the most common pathogen in fungal IE caused by non-Aspergillus filamentous fungi.⁸ The pathology of Scedosporium species varies widely, ranging from respiratory colonization in cystic fibrosis patients and localized subcutaneous tissue infections to life-threatening disseminated infections.³ Because clinical symptoms, histopathology, and imaging features of scedosporiosis are easily confused with other mycoses, such as aspergillosis and fusariosis, the diagnosis of scedosporiosis is difficult, resulting in delayed optimal treatment and increased mortality.

Among the 71 Australian clinical isolates of Scedosporium species associated with colonization and infection, Scedosporium apiospermum accounted for 59.2% and Scedosporium aurantiacum for 40.8%.⁹ However, among the 45 clinical isolates of Scedosporium infection in China, Scedosporium boydii was the most prevalent species at 48.9%, followed by S. apiospermum at 40%, S. aurantiacum at 8.9%, and Scedosporium dehoogii at 2.2%.⁴ This distribution is similar to that observed in patients with cystic fibrosis (CF) in France and in patients with CF or immunocompromise in Northern Spain.^10,11 Among the 28 cases of immunocompetent patients reported globally who were deeply infected with Scedosporium species, S. apiospermum was the most common species at 75%, followed by S. boydii at 17.9% and S. aurantiacum at 10.7%.¹²

Based on the initial laboratory investigations and epidemiological studies described above, S. apiospermum was the first pathogen to be identified in our patient. However, S. aurantiacum was identified based on macroscopic characteristics, including the production of a distinctive light-yellow pigment and growth at 45 °C, as well as microscopic features manifested as mostly obovoid conidia, and by MALDI-TOF MS and nanopore sequencing of ITS1. Additionally, the assimilation of d-ribose, but not sucrose, is the key characteristic for discriminating S. aurantiacum from S. apiospermum.¹³

Since S. aurantiacum was proposed as a new phylogenetic species in 2005,¹⁴ there has been an increase in S. aurantiacum cases involving local or invasive infections. Based on case reports available in PubMed, we identified and analyzed 15 cases of S. aurantiacum infection from 2005 to 2025, after including our case, as summarized in Table 1.^15–26

Table 1 Summary of Reported Cases of Scedosporium aurantiacum Infection 2005–2025

Among the 15 patients, there were 7 males and 8 females. The age of these patients ranged from 4 to 82 years. There were 10 cases in Asia, two in America, two in Europe, and one in Australia. S. aurantiacum infection in these patients was associated with a diversity of risk factors and initial events, including trauma (5 cases, 33.3%), organ transplantation (4 cases, 26.7%), near-drowning experience (3 cases, 20%), diabetes (2 cases, 13.3%), malignant lymphoma (1 case, 6.7%), lung cancer (1 case, 6.7%), acute myeloid leukemia (1 case, 6.7%), chronic bronchiectasis (1 case, 6.7%), history of nontuberculous mycobacterial infection (1 case, 6.7%), neutropenia (1 case, 6.7%), and anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (1 case, 6.7%). The interval from the initial event to onset among the 8 cases ranged from 0 days to 3 months. Fever was the most common systemic symptom (7 cases, 46.7%), followed by altered consciousness (5 cases, 33.3%) and respiratory distress (5 cases, 33.3%). The main sites of infection were the lungs (7 cases, 46.7%), brain (5 cases, 33.3%), blood and eye (each accounted for 3 cases, 20%). Other affected sites included the bones, subcutaneous tissues, and transplanted kidney (each accounted for 2 cases, 13.3%), and the native heart and transplanted heart (each accounted for 1 case, 6.67%). Five patients (33.3%) had a disseminated disease. Among them, three patients had a history of organ transplantation, 1 case involved trauma, and 1 case involved near-drowning.

There were eight immunocompromised patients (53.3%) and seven immunocompetent patients (46.7%). Generally, immunocompromised patients are thought to be predisposed to opportunistic Scedosporium infection; however, this review revealed a high incidence of S. aurantiacum infection in immunocompetent patients due to prior trauma (4 cases, 26.7%) and near-drowning (3 cases, 20%). This finding suggests the need to maintain a high index of clinical suspicion in patients with a history of exposure to contaminated environments, even if they are immunocompetent. In the current case, our patient was previously healthy. Despite extensive investigation, there was no evidence of immunosuppression and immunodeficiency in our patient. We presumed that the source of his disseminated infection and endocarditis was through traumatic inoculation in his lumbar after exposure to wastewater. The incidence of lung infections in immunocompromised patients (4 out of 8, 50%) was higher than that in immunocompetent patients (2 out of 7, 28.6%). Immunocompromised patients (3 out of 8, 37.5%) were also more likely to develop disseminated infection than immunocompetent patients (2 out of 7, 28.6%). To date, there have been no reported cases of subcutaneous soft tissue infection in immunocompetent patients.

Of note, only our patient’s native heart valves were affected, while the other patient was a heart transplant recipient who acquired S. aurantiacum through donor-derived transmission.¹⁸ Furthermore, S. aurantiacum endocarditis may have a poor prognosis. Previous studies have shown that in mouse models, the virulence of S. aurantiacum is stronger than that of other Scedosporium species and is comparable to that of Lomentospora prolificans, which has a high mortality rate of 81% in patients with endocarditis.^27,28 In this review, the overall mortality of S. aurantiacum infection was 46.6% (7 out of 15), but the mortality in patients with disseminated infection can reach up to 80% (4 out of 5). Hence, the clinical outcomes of disseminated infections caused by S. aurantiacum are discouraging.

Voriconazole is recommended by the European Federation of Medical Mycology as a first-line antimycotic drug for the treatment of Scedosporium infections.²⁹ Although voriconazole was used within the recommended dose in our patients, we did not monitor the serum voriconazole concentrations periodically during the course of intravenous therapy. However, this is an essential procedure for ensuring individualized medication, maximizing therapeutic efficacy and minimizing toxicity. In this case, we used voriconazole combined with amphotericin B (Lipid Complex) to combat S. aurantiacum infection. This combination therapy is a first-line alternative treatment for scedosporiosis. However, the optimal therapy remains unknown and data on treatment is anecdotal. Several case reports have added to the evidence that the combination therapy with voriconazole and terbinafine may be synergistic and effective for the treatment of scedosporiosis.^30–32 So far, there have been no reports on the use of voriconazole in combination with terbinafine for the treatment of S. aurantiacum infection. Goldman et al reported a case of cutaneous S. apiospermum infection, and the patient partially recovered through the combination therapy of voriconazole plus micafungin and granulocyte macrophage colony-stimulating factor (GM-CSF).³³ In this review, only one patient recovered through skin puncture of a subcutaneous abscess, but without using antifungal drugs.¹⁹ Among the remaining 14 patients who received antifungal treatment, 11 patients were administered voriconazole (11 out of 14, 78.6%), and most of them (7 out of 11, 63.6%) had improved outcomes, while all 3 patients who did not use voriconazole died.

Among the 7 improved cases, the treatment duration ranged from 12 to 215 days. Nine patients (9 out of 15, 60%) underwent in vitro antifungal susceptibility testing of S. aurantiacum. The results showed that voriconazole was the most active agent with a minimum inhibitory concentration (MIC) range from 0.25 to 1 μg/mL, followed by a MIC range of 0.5->16 μg/mL for posaconazole, 0.5->16 μg/mL for itraconazole, 2->16 μg/mL for amphotericin, 2->16 μg/mL for terbinafine, 2->16 μg/mL for isavuconazole, 4->8 μg/mL for micafungin and 4->16 μg/mL for caspofungin.

Because of the variability in virulence and antifungal susceptibility patterns among different species, accurate identification of Scedosporium species at the species level is very important for clinical practice.^2,34 Although little is known about the pathogenesis and virulence of Scedosporium species, recent studies have shown that the biofilms serves as a protective role, and the ability to form biofilms enhances virulence in Scedosporium species.^35,36 The biofilms formed by S. aurantiacum were more robust and had a greater biomass than those formed by S. apiospermum, and the clinical S. aurantiacum isolate was also more virulent in a larvae Galleria mellonella infection model.³⁵ By comparing the clinical presentation of S. aurantiacum and S. apiospermum in immunocompetent patients, we found that apart from fever and local pain, which were the most common clinical presentation for both, dyspnea and altered consciousness occurred more common in patients infected with S. aurantiacum compared to those infected with S. apiospermum, while haemoptysis and lethargy occurred more common in patients infected with S. apiospermum compared to those infected with S. aurantiacum.¹² In immunocompetent individuals, patients infected with S. aurantiacum may have a poorer clinical prognosis than those infected with S. apiospermum, with the mortality rates being 28.6% and 23.8%, respectively.

Currently, culture remains the main method for detecting pathogens in clinical samples. Although it is difficult to distinguish these species in terms of morphology, molecular biological methods, such as polymerase chain reaction (PCR) for use on tissue specimens and sequencing of ITS1, ITS2, β-tubulin, and calmodulin for use in cultures, are widely used for the identification of Scedosporium species with extremely high sensitivity and precision.³⁷ Clinically, MALDI-TOF MS is a reliable tool that can rapidly and accurately identify Scedosporium species.³⁸ Nanopore sequencing technology, as an important auxiliary diagnostic method for difficult-to-cultivate pathogens and uncommon pathogens, has the advantages of short turnaround time, high sequencing length, precise results, and applicability to various clinical samples.³⁹

Conclusion

Herein, we report the first case of S. aurantiacum endocarditis in China. This case highlights that, even in immunocompetent patients, fungal origin should be suspected, especially in those with a history of exposure to a contaminated environment. Adequately obtaining the exposure history of contaminated environments is an important aspect of clinical practice, which could assist clinicians to avoid delayed diagnosis. Nanopore sequencing offers a new option for identifying S. aurantiacum. It is crucial for clinical laboratories to identify Scedosporium spp. to the species level and perform drug susceptibility testing to determine the most appropriate antimycotic agent. Accurate diagnosis and rational treatment are associated with low mortality rate.